The alpha7 nicotinic acetylcholine receptor (?7nAChR) has emerged as a unique player in the infection and progression of COVID-19, which has caused more than 325,000 deaths. ?7nAChR links tobacco smoking to major clinical manifestations in COVID-19, including respiratory infection, anosmia, systemic coagulopathy, and cytokine storm. Several sequences of SARS-CoV-2 are found to be homologous to ?-bungarotoxin and ?- cobratoxin, potent antagonists of ?7nAChR. These findings support the hypothesis that SARS-CoV-2 interacts directly with ?7nAChR, inhibits its function, and consequently dysregulates the inflammatory responses mediated by ?7nAChR. The experimental evidence is urgently needed to correctly establish the role of ?7nAChR in COVID-19 and to understand nicotine?s detrimental or protective effects on the onset and progression of COVID- 19. With permission from the NIDA (Dr. Roger Little, Deputy Director, Division of Neuroscience and Behavior), we seek Administrative Supplement support to address several key questions about the involvement of nicotine and ?7nAChR in COVID-19. Specifically, we propose to elucidate: (1) where and how SARS-CoV-2 proteins interact with ?7nAChR and how nicotine alters such interactions; and (2) how SARS-CoV-2 proteins affect intracellular signaling pathways downstream of ?7nAChR that lead to upregulation and transactivation of pro- inflammatory cytokines, and how nicotine modulates the outcome of this process. Considering the widespread expression of ?7nAChR in various organs and the significant regulatory role of ?7nAChR in the cholinergic anti- inflammatory pathway, our research outcomes can potentially lead to new treatment strategies to combat COVID-19.